tretinoin and Hematologic-Diseases

Several phase II clinical studies of all-trans-retinoic acid (ATRA) have been conducted in acute promyelocytic leukemia (APL), an uncommon subtype of acute myeloid leukemia (AML). ATRA has been shown to induce complete remission (CR) in 64% to 96% of patients with APL, and with rapid resolution of the coagulopathy, which is a major cause of early morbidity and mortality. Although CRs induced with ATRA alone are usually not sustained and intensive antileukemic consolidation therapy is required to prolong remission, these findings indicate that a new approach of differentiation therapy is effective in treating patients with APL and may potentially be effective in other malignancies. The presence of the PML/retinoic acid receptor-alpha (PML/RAR-alpha) fusion gene, produced as a result of the unique chromosomal translocation in APL, is a marker of sensitivity to ATRA. Aside from the complications of hyperleukocytosis and the retinoic acid syndrome, ATRA therapy is generally well tolerated. An international study (Intergroup 0129), headed by the Eastern Cooperative Oncology Group, is currently under way to determine further the role of ATRA in the treatment of patients with APL. Given its success in APL, studies of ATRA in other hematologic malignancies are also being conducted. A better understanding of how retinoids modulate carcinogenesis will help determine if the results in APL can be realized in other malignancies treated with ATRA or other retinoids.

Topics: Clinical Trials, Phase II as Topic; Disseminated Intravascular Coagulation; Forecasting; Hematologic Diseases; Humans; Leukemia, Promyelocytic, Acute; Remission Induction; Tretinoin

The antitumor effect of different retinoids focused attention in the treatment of malignant disorders on different pathways. The therapeutic effect was proved in acute promyelocytic leukaemia, but was limited in juvenile form of chronic myeloid leukaemia and in acute myelomonocytic and monoblastic leukaemia. Combined with different leukostatics, long remission could be achieved. The most important therapeutic pathway is direct growth inhibition with and without cell differentiation. Clinically, retinoids are effective in tumours, like: cutan T-cell lymphoma, mycosis fungoides, Sézary syndrome, oral leukoplakia (prevention of head and neck cancer metastases), variant form of small lung cell carcinoma, oestrogen dependent breast-carcinoma and cervix-carcinoma. The most serious complication of the retinoids' administration is the retinoic acid syndrome which is followed sometimes with thromboembolic events. Retinoids are teratogenic and hepatotoxic.

Topics: Blood Coagulation Disorders; Hematologic Diseases; Hematopoietic System; Humans; Leukemia; Neoplasms; Retinoids; Thromboembolism; Tretinoin

The evaluation of new therapies in prostate cancer requires unique end points for agents with diverse mechanisms of action. Because retinoic acid may have a confounding effect on prostate-specific antigen, we incorporated a pathological end point into the outcome assessment of two sequential clinical trials using all-trans-retinoic acid (ATRA) and the combination of 13-cis-retinoic acid and IFN-2a (cRA¿IFN). Pre- and posttherapy tumor biopsy specimens were studied for histological changes, apoptosis (terminal deoxynucleotidyl transferase-mediated nick end labeling assay), and proliferation index (Ki67). Prostate-specific membrane antigen (PSMA) expression was also evaluated using two different monoclonal antibodies to its intracellular domain (Cytogen 7E11 and Hybritech PM2). Fourteen patients with androgen-independent disease were treated with ATRA (50 mg/m2 p.o. every 8 h daily) and 16 androgen-independent and 4 androgen-dependent patients were treated with cRA¿IFN (10 mg/kg/day cRA plus 3, 6, or 9 million units daily IFN). Both therapies were well tolerated, with fatigue and cheilitis being the most common adverse events. Clinical activity, assessed by radiographs and serum prostate-specific antigen, was minimal, and the majority of patients progressed within 3 months. One patient with androgen-dependent disease had prolonged stabilization for >1 year. The majority of cases (95%) showed no gross histological changes and no difference in apoptotic or proliferative indices. Increased PSMA immunoreactivity was seen in seven of nine (78%) cases using PM2 antibody and in two of nine (22%) cases using the 7E11 antibody. Although antitumor effects were modest, the results suggest a role for retinoids in modulating the expression of PSMA on prostate cancer cells.

Topics: Aged; Antigens, Surface; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Biopsy; Bone Neoplasms; Carboxypeptidases; Cheilitis; Dyspnea; Exanthema; Fatigue; Glutamate Carboxypeptidase II; Hematologic Diseases; Humans; Interferon alpha-2; Interferon-alpha; Ki-67 Antigen; Liver; Male; Middle Aged; Prostate; Prostate-Specific Antigen; Prostatic Neoplasms; Recombinant Proteins; Transaminases; Treatment Outcome; Tretinoin

We administered liposome-encapsulated all-trans retinoic acid (L-ATRA) to 48 patients with refractory hematologic malignancies using an every-other-day schedule for 28 days and doses of 15 to 175 mg/m2. In 19 patients, pharmacology studies were conducted after the first (day 1) and seventh (day 15) doses. In contrast to the decline in tretinoin concentration seen within 3 to 4 days of administration of daily oral ATRA, there were no differences between the area under the curve (AUC) of tretinoin concentration versus time on day 1 and day 15 (P = .98, Wilcoxon signed-rank test). Peak day 1 concentrations after 15 mg/m2 were higher than those reported after 45 mg/m2 oral ATRA. Six patients with relapsed acute promyelocytic leukemia (APL) were treated. Three, each in first relapse and at least year from the last exposure to oral ATRA, achieved a complete response (CR). Disease recurred in two (one at 3 months despite maintenance L-ATRA and similarity in tretinoin AUC on days 1 and 85, and the other at 5 months, 2 months after discontinuation of L-ATRA) and the third was transplanted 1 month into CR. The three nonresponders were in at least a second relapse and failed to respond to oral ATRA before or immediately after receiving L-ATRA. Severe toxicity developed in three of eight patients treated at 175 mg/m2 (joint pains in two, skin in one). The maximum tolerated dose (MTD) was determined to be 140 mg/m2, at which dose grade 2 toxicity (primarily headache and skin) occurred in eight of eight patients, but grade 3 to 4 toxicity in none. Compared with oral ATRA, L-ATRA apparently results in greater exposure to tretinoin and for a longer time.

Topics: Drug Carriers; Hematologic Diseases; Humans; Leukemia, Myeloid, Acute; Liposomes; Neoplasms; Recurrence; Tretinoin

Topics: Adolescent; Antineoplastic Combined Chemotherapy Protocols; Arsenic Trioxide; Child; Child, Preschool; Female; Hematologic Diseases; Humans; Leukemia, Promyelocytic, Acute; Male; Tretinoin

The application of all-trans-retinoic acid (ATRA) in the protocols of treatment of acute promyelocyte leucosis provided the achievement of 95% of full remissions and fast correction of coagulopathy. Besides, ATRA along with positive impact can exert the side effects, among which the most dangerous is the differentiation syndrome. On the basis of analysis of clinical signs, biochemical, hemostasiologic and morphologic blood indicators it is established that among prognostic criteria of differentiation syndrome development are presence of febrile temperature, decrease of content of thrombocytes lesser than 20-109/l (deep degree of thrombocytopenia), prolongation of index of activated partial thromboplastin time relative to norm before treatment start. Apart from this, the following factors also are among such kind of criteria: decrease of hemoglobin after ATRA prescription before differentiation syndrome development, on-going hypofibrinogenemia and deep degree of thrombocytopenia under concurrent increase of content of urea and creatinine as compared with initial values in treatment dynamics.

Topics: Adolescent; Adult; Aged; Blood Cell Count; Cell Differentiation; Female; Hematologic Diseases; Humans; Leukemia, Promyelocytic, Acute; Male; Middle Aged; Tretinoin

Topics: Animals; Chemical and Drug Induced Liver Injury; Diterpenes; Etretinate; Hematologic Diseases; Liver; Male; Rats; Rats, Inbred Strains; Retinyl Esters; Tretinoin; Vitamin A